About a quarter of patients with severe aplastic anemia remain pancytopenic despite immunosuppressive therapy, and others have suboptimal responses in at least one lineage. We have developed a program to ask whether use of a drug stimulating the c-mpl receptor, which binds the endogenous hormone thrombopoietin, could stimulate human hematopoietic stem cells in vivo. Murine, our own rhesus, and human data all suggest that thrombopoietin can stimulate primitive hematopoietic stem and progenitor cells to expand. The small molecule oral thrombopoietin mimetic eltrombopag was initially developed to overstimulate platelet production from marrow megakaryocytes to compensate for immune platelet destruction. We developed a protocol utilizing eltrombopag in a phase 1/2 clinical trial for patients with refractory severe aplastic anemia. We initially reported that eltrombopag had efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses. During the current reporting period, we reported safety and efficacy data on a further 18 patients and long-term follow-up on the entire cohort of 43 patients. The overall response rate was 17 of 43 patients (40%) at 3 to 4 months, including tri- and bilineage responses. The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell, and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range, 9-37 months), and all maintained stable counts a median of 13 months (range, 1-15 months) off eltrombopag. Eight patients, including 6 nonresponders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. None evolved to acute myeloid leukemia to date. We initiated a new study, asking whether more prolonged administration of eltrombopag, for 6 months instead of 3 months, would improve response rate and rescue a larger fraction of refractory patients. This protocol is ongoing and has already accrued more than half of its target patients (22). To date, response rates appear higher than in the initial trial. Samples from these patients are being utilized to investigate pharmacokinetics of the drug in this patient population, and in collaboration with Dr. Neal Young's and Dr. Andre Larochelle's research groups, to investigate the impact of this treatment on genetic abnormalities in marrow failure, and on in vivo and in vitro stem cell expansion. This program recently resulted in FDA approval of a new labeled indication for eltrombopag, for treatment of refractory aplastic anemia. This is the first new drug approved for aplastic anemia in decades and the first drug approved specifically for the refractory aplastic anemia patient population. These trials have now also expanded to treating a number of other bone marrow failure patient populations, as detailed in Dr. Neal Young's report.